Recently, problems with pathogens such as viruses and pathogenic proteins, which may possibly exist as contaminants in a solution for injection, have been highlighted as a critical situation. This is especially true when a liquid preparation containing a physiologically active substance such as plasma derivatives, biopharmaceuticals or plasma for transfusion is administered into a human body. A method for removing or inactivating such pathogens is required.
Methods for inactivating viruses include heating processes and treatments using chemical agents (for example solvent/detergent (S/D) treatment). However, these methods are limited in their inactivation effects depending on types of viruses. For example, a heating process is less effective for thermostable viruses such as hepatitis A virus. Further, an S/D treatment has virtually no effect on viruses such as parvovirus which have no lipid membrane. In a treatment using chemical agents, since there is a possibility that the chemical agent used may be administered into a human body, a process for removing the chemical agent may be required.
Membrane filtration is known as a method for physically removing viruses. Since a procedure for separation is performed using a membrane filtration system which is dependent on a size of virus particles, it is effective for all viruses regardless of chemical or thermal natures of viruses.
A type of virus ranges from the smallest viruses such as parvovirus having a diameter of about 18–24 nm or poliovirus having a diameter of about 25–30 nm to a relatively large virus such as HIV having a diameter of 80–100 nm. In order to remove such groups of viruses by physical means using the membrane filtration, a microporous membrane having a maximum pore diameter of 100 nm or less is required. The need for a system for removing small viruses such as parvovirus has been increased recently.
Virus removal membrans, which can be used for purification of plasma derivatives and biopharmaceuticals by removing viruses, must have not only viral removal ability but also a high permeability for physiologically active substances such as albumin and globulin. For such purposes, ultrafiltration membranes having a pore diameter of several nm and reverse osmotic membranes having a smaller size of pore diameter are not suitable as a virus removal membrane.
Even if microporous membranes have a pore diameter suitable for the viral removal, the microporous membranes, such as an ultrafiltration membrane, having large voids inside the membrane and carrying appropriate filtration characteristics in a surface skin layer, have a low reliability for viral removal. The reason is that there are always significant deficiencies such as pinholes or cracks in the skin layer and large voids inside the membrane. The skin layer herein means an extremely thin layer existing on one side or both sides of the membrane, and having a dencer structure as compared with an inner region of the membrane.
A membrane constructed with a gradient structure with continuously increasing pore diameter from one side of the membrane surface to the other is not suitable for viral removal. In order to perform the viral removal completely, the membrane must have a structure in which a homogeneous structural region having no large internal void as well as having extremely few or almost no continuous change in a pore diameter along a thickness direction, is present with a certain thickness. In such a structure, a mechanism of filtration generally called “depth filtration” is generated. As a result, a highly reliable viral removal capability can be obtained as a sum of the viral removal in each minute region of a membrane thickness.
During a final process of manufacturing, a microporous membrane to be used for the viral removal is treated with some sterilization treatment in order to guarantee safety of the product. Sterilization procedures used include: a method using chemical agents, a method using ultraviolet irradiation or γ-ray irradiation, a method using steam sterilization and the like. Use of chemical agents may exert harmful effects on a human body caused by residual trace chemical agents remaining in a microporous membrane. A sterilization method using ultraviolet irradiation is not suitable for sterilization in the final process due to a low transmissivity of ultraviolet rays. A sterilization method using γ-ray irradiation is unreliable due to irradiation damage caused in a microporous membrane. It seems that use of steam is the most secure, reliable and preferable method. In this case, materials used in a microporous membrane are required to have a thermal stability, since the membrane should be treated by the steam sterilization at high temperature.
In order to prevent adsorption of protein, a component of a preparation, to a microporous membrane, the membrane should preferably be hydrophilic. Consequently, it is preferable to use membrane materials that are originally hydrophilic or to introduce hydrophilic nature into the membrane by a post-treatment. However, when hydrophilic materials are used, there is a possibility of remarkable deterioration in mechanical properties of the membrane due to swelling of the membrane with water. Consequently, it is preferable to prepare a hydrophilic microporous membrane firstly by constructing a physical structure of the membrane with hydrophobic materials, and thereafter hydrophilizing the surface of micropore of the constructed membrane.
In a case of industrial production of plasma derivatives and biopharmaceuticals, it is preferable to use a membrane having a high permeation rate for a solution containing physiologically active substances in order to increase productivity. However, a solution containing physiologically active substances such as globulin contains large amounts of suspended substances as polymers such as dimers or more. These suspended substances cause clogging of pores of a microporous membrane. As a result, filtration rate is rapidly decreased. The smaller the size of the micropore diameter, the more this tendency is significantly increased. As a result, filtration resistance is sometimes rapidly increased due to an accumulation of the suspended materials on a membrane surface. In order to reduce the inconvenience, a pre-filter with larger pore diameter is conventionally used to remove the suspended substances. However, it is difficult to remove the suspended substances completely by using a pre-filter. In addition, since use of two types of filters results in an increased cost, a membrane which does not result in clogging in the presence of the suspended substances, is eagerly demanded.
JP-A-7-265674 discloses a polyvinylidene fluoride membrane which can be used for the viral removal from a solution, and a term “isotropic” is used in the claims thereof. However, the “isotropic” membrane often had a problem of drastic decrease in treatment amount due to clogging or accumulation of the suspended substances onto a membrane surface, because a liquid for which the microporous membrane is used for the purpose of viral removal generally contains physiologically active substances and thus a variety of suspended substances.
WO 99/47593 discloses a polyvinylidene fluoride membrane which has a surface layer with improved open pore ratio by using a specified cooling medium, and describes that said surface layer can have a pre-filtering function. However, the thickness of said surface layer is not greater than 3 μm, resulting in the problem of not exhibiting a sufficient pre-filtering effect during filtration of a liquid containing a variety of suspended substances such as protein solutions.
JP-A-7-173323 discloses a polyvinylidene fluoride microporous membrane manufactured by making a difference between cooling rates at both membrane surfaces from each other in a cooling process. Under this condition, a pore diameter at the surface cooled at slower rates becomes larger, and thus providing a difference between pore diameters on each surface of the membrane. A pore diameter ratio of both membrane surfaces is specified as 4–10 in the claims of said publication. In the method according to said publication, cooling speed varies continuously along a membrane thickness direction, providing a continuous change in a membrane structure along a membrane thickness direction, and further a noticeable gradient structure having a pore diameter difference of over four times between both membrane surfaces. In such a manufacturing method, a fine structure layer which has a highly accurate homogeneity to realize a depth filtration required for the viral removal, cannot be obtained.
WO 91/16968 discloses, as a polyvinylidene fluoride membrane to be used for the viral removal from a solution, a microporous membrane comprising a supporting body, a surface skin and an intermediate porous region present between the supporting body and the skin, produced by coating and coagulating a polymer solution on the supporting body having pores and thus forming the skin layer and the intermediate porous layer onto said supporting body. However, said microporous membrane does not have a one-piece structure nor a fine structure layer of the present invention.